Accurately balancing the competing risks of interventional treatment and natural history - primarily intracranial hemorrhage (ICH) - is necessary for optimal management of patients harboring brain arteriovenous malformations (bAVMs). The overarching theme of this project is to develop novel risk-stratification biomarkers and provide a decision-analysis framework for their use. As a class, unruptured patients are at higher risk for treatment-related injury but at lower risk for ICH. Accordingly, treatment of unruptured bAVMs-half of all cases- is becoming increasingly controversial. The ongoing randomized clinical trial (NCT00389181), A Randomized Trial of Unruptured Brain AVMs (ARUBA), is comparing best intervention (either surgery, embolization and/or radiosurgery) vs. non-intervention. If non-intervention is found superior-or even non- inferior-then there will be even greater demand to risk-stratify unruptured cases, as good ICH risk predictors are lacking in this group. Taken together, there is a pressing need to improve risk assessment. Aim 1 will demonstrate that Silent Intralesional Microhemorrhage (SIM) is a novel risk factor for bAVM rupture. We will show that microscopic evidence of hemosiderin (hemosiderin positivity) in resected bAVM tissue is associated with index ICH (clinical presentation with ICH. Further we will show that macrophage infiltration is highly correlated with hemosiderin positivity, which represents an additional potential biomarker. In addition to use as risk markers, both SIM and macrophage infiltration might also serve as surrogate endpoints for clinical trials. Aim 2 will develop a MR biomarker for SIM, showing that hemosiderin positivity in resected tissue is correlated with susceptibility effect on pre-treatment iron-sensitive imaging (ISI). Using a prospective cohort with a mean follow-up of 2.5 years, we will estimate SIM incidence and compare it to known symptomatic ICH rates. A potential additional marker, macrophage infiltration, can also be imaged in patients using ferumoxytol, an UltraSmall Particles of Iron Oxide (USPIO); MR imaging of ferumoxytol uptake will predict tissue macrophages burden in resected tissue. In Aim 3, we will demonstrate that (a) genetic variants in IL1ss and TNF are predictors of new ICH after diagnosis; (b) endoglin (ENG) genotype is associated with worsened outcome after index ICH; (c) BDNF genotype is associated with worsened functional outcome after surgical resection in unruptured cases; and (d) Using our existing Genome-Wide Association Study dataset, we will identify novel risk predictors for new ICH, outcome after ICH and outcome after resection. We will sequence novel loci to identify variants associated with these outcomes and test in our entire cohort. Aim 4 will construct a practical system to balance risks and benefits to optimally inform bAVM management and contextually evaluate and combine new knowledge from Aims 1-3 with established risk markers. We hypothesize that addition of novel risk factors will provide further improvement in discrimination of risk. The proposed project will undergird future multi-center efforts to improve care for bAVM patients.